This application describes a comprehensive biochemical study of the regulation of calmodulin activity. Calmodulin, a calcium-binding protein, has been shown to mediate the calcium activation of many enzymes and physiological processes. Preliminary experiments have indicated that calmodulin undergoes two types of post-translational modification - N-methylation and carboxymethylation, which accompanies tardive dyskinesia, is related to an increase in membrane-bound calmodulin. We will investigate the N-methylation and carboxymethylation of calmodulin in an attempt to determine the functional sugnificance of these alterations in calmodulin structure. In other studies we will examine the regulation and enzymology of calmodulin regulation, the factors responsible for binding of calmodulin to neural membranes, and the factors which govern calmodulin biosynthesis and degradation. The effects of acute and chronic administration of neuroactive drugs affecting receptor sensitivity on these aspects of calmodulin modification, function and synthesis will be determined.